The delta-5 and delta-6 desaturases (encoded by FADS1 and FADS2, respectively) are essential for biosynthesis of long-chain omega-3 and omega-6 fatty acids. These long-chain polyunsaturated fatty acids (LCPUFA), such as docosahexaenoic acid (DHA) and arachidonic acid (ARA), are major components of cell membranes in the central nervous system, act as precursors for signaling molecules such as eicosanoids and docosanoids, and directly affect gene expression to influence important physiological functions such as inflammation and blood clotting1-3. Although both ARA and DHA can be obtained pre-formed through diet, most populations do not consume enough to completely remove any dependence on biosynthesis. Indeed, genetic studies have underscored the importance of FADS1 and FADS2 by linking single nucleotide polymorphisms (SNPs) in these genes with numerous health outcomes, including coronary artery disease, total cholesterol, LDL, C-reactive protein levels, allergy and atopic eczema, as well as cognitive outcomes such as attention-deficit hyperactivity disorder and IQ in children4-9.
However, mechanisms describing how gene variants affect FADS gene function are lacking, so it is difficult to translate polymorphism associations into disease prevention or treatment. Despite numerous Polymorphisms in FADS2 associated with health outcomes, there are no validated non-synonymous Polymorphisms in the FADS2 gene. This suggests that mechanisms are likely to be regulatory rather than through protein structural changes for any causal Polymorphisms in FADS2. A causal polymorphism in the promoter region of FADS2 has been reported10, but this polymorphism is not polymorphic in the Han Chinese, Japanese, and Yoruba International HapMap project populations (HapMap Genome browser release #28). Thus, this one polymorphism does not explain all associations found in other world populations. In addition, this polymorphism only affects FADS2 expression, so it does not explain results in European or majority European-descendent populations suggesting lower Δ5-desaturase activity associated with some Polymorphisms11-13.
Some key molecules involved in regulation of FADS1 and FADS2 gene expression have been identified, but regulatory regions and functional binding sites within these genes have not been fully elucidated. The FADS genes reside as a cluster on chromosome 11 consisting of FADS1, FADS2 and a third putative desaturase designated FADS3. All reported mechanisms for regulation, such as dietary fatty acid or hormonal responses, affect both FADS1 and FADS2 in concert. For example, the end-product DHA is known to down-regulate expression of both FADS1 and FADS2 by lowering activity of the sterol response element binding protein 1c (SREBP-1c)14. Other transcription factors that have been implicated in regulation of FADS genes include the peroxisome proliferator-activated receptors (PPARs)15. However, no information is available to link specific Polymorphisms and phenotypes with response to specific transcription factors.
Therefore, there exists a great need to identify proper subjects of certain polymorphisms, better modulate FADS expression in these subjects, and hence better regulate biosynthesis of LCPUFA therein.